Height and cancer risk in East Asians: Evidence from a prospective cohort study and Mendelian randomization analyses.

BACKGROUND: Height is associated with increased cancer risk, but most studies focus on Western populations. We aimed to evaluate this relationship in East Asians. METHOD: Observational analyses were performed utilizing data from China Kadoorie Biobank (CKB) prospective cohort. Adjusted hazard ratios (HRs) and corresponding 95 % confidence intervals (CIs) were estimated using Cox proportional hazards models. Two-sample Mendelian randomization (MR) analyses explored causal effects between height and cancer using data from Korean Genome and Epidemiology Study (KoGES), Biobank Japan (BBJ), and CKB. RESULTS: Over a median 10.1-years follow-up, 22,731 incident cancers occurred. In observational analyses, after Bonferroni correction, each 10 cm increase in height was significantly associated with higher risk of overall cancer (HR 1.16, 95 % CI 1.14-1.19, P < 0.001), lung cancer (1.18, 95 % CI 1.12-1.24, P < 0.001), esophageal cancer (1.21, 95 % CI 1.12-1.30, P < 0.001), breast cancer (1.41, 95 % CI 1.31-1.53, P < 0.001), and cervix uteri cancer (1.29, 95 % CI 1.15-1.45, P < 0.001). Each 10 cm increase in height was suggestively associated with increased risk for lymphoma (1.18, 95 % CI 1.04-1.34, P = 0.010), colorectal cancer (1.09, 95 % CI 1.02-1.16, P = 0.010), and stomach cancer (1.07, 95 % CI 1.00-1.14, P = 0.044). In MR analyses, genetically predicted height (per 1 standard deviation increase, 8.07 cm) was suggestively associated with higher risk of lung cancer (odds ratio [OR] 1.17, 95 % confidence interval [CI] 1.02-1.35, P = 0.0244) and gastric cancer (OR 1.14, 95 % CI 1.02-1.29, P = 0.0233). CONCLUSIONS: Taller height was significantly related to a higher risk for overall cancer, lung cancer, esophageal cancer, breast cancer, and cervix uteri cancer. Our findings suggest that height may be a potential causal risk factor for lung and gastric cancers among East Asians.

Association of sleep traits with benign prostatic hyperplasia in middle-aged and elderly men: A prospective analysis in UK Biobank.

AIMS: The association of sleep traits (insomnia, sleep duration, chronotype, daytime sleepiness, and snoring) with benign prostatic hyperplasia (BPH) is unclear. This research aimed to examine the effects of sleep traits on BPH risk. METHODS: A total of 170 241 men aged 38 to 73 years from UK Biobank were included. An overall healthy sleep score was created based on five sleep traits. A Cox regression model was utilized to compute adjusted hazard ratios (HRs) and population attributable fractions (PAFs) with 95% confidence intervals (CIs) for BPH risk in relation to sleep traits. RESULTS: During a median of 12.0 years follow-up, 13 026 incident BPH cases occurred. We observed that sleep duration (7-8 h/d; HR 0.95; 95% CI 0.92-0.99), no frequent insomnia (HR 0.71; 95% CI 0.69-0.74), and no frequent daytime sleepiness (HR 0.86; 95% CI 0.79-0.93) were significantly related to reduced BPH risk. Each one-point increment of the healthy sleep score was related to a decreased BPH risk, with an adjusted HR of 0.90 (95% CI 0.89-0.92). The multivariable-adjusted HR in men adopting five versus zero to one low-risk sleep traits was 0.68 (95% CI 0.61-0.75) for BPH risk. Estimates of the PAF indicated that 9.1% (95% CI 5.8-12.5%) of BPH cases would be prevented if all individuals had adopted all five low-risk sleep traits, assuming causality. CONCLUSIONS: Our study indicates an association between a healthy sleep pattern and a lower risk of BPH, emphasizing the importance of adhering to such patterns for potentially reducing BPH risk. Geriatr Gerontol Int 2024; 24: 675-682.

Promotion of Lung Cancer Metastasis by SIRT2-Mediated Extracellular Protein Deacetylation.

Acetylation of extracellular proteins has been observed in many independent studies where particular attention has been given to the dynamic change of the microenvironmental protein post-translational modifications. While extracellular proteins can be acetylated within the cells prior to their micro-environmental distribution, their deacetylation in a tumor microenvironment remains elusive. Here it is described that multiple acetyl-vWA domain-carrying proteins including integrin ß3 (ITGB3) and collagen 6A (COL6A) are deacetylated by Sirtuin family member SIRT2 in extracellular space. SIRT2 is secreted by macrophages following toll-like receptor (TLR) family member TLR4 or TLR2 activation. TLR-activated SIRT2 undergoes autophagosome translocation. TNF receptor associated factor 6 (TRAF6)-mediated autophagy flux in response to TLR2/4 activation can then pump SIRT2 into the microenvironment to function as extracellular SIRT2 (eSIRT2). In the extracellular space, eSIRT2 deacetylates ITGB3 on aK416 involved in cell attachment and migration, leading to a promotion of cancer cell metastasis. In lung cancer patients, significantly increased serum eSIRT2 level correlates with dramatically decreased ITGB3-K416 acetylation in cancer cells. Thus, the extracellular space is a subcellular organelle-like arena where eSIRT2 promotes cancer cell metastasis via catalyzing extracellular protein deacetylation.

Using machine learning for mortality prediction and risk stratification in atezolizumab-treated cancer patients: Integrative analysis of eight clinical trials.

BACKGROUND: Few models exist to predict mortality in cancer patients receiving immunotherapy. Our aim was to build a machine learning-based risk stratification model for predicting mortality in atezolizumab-treated cancer patients. METHODS: Data from 2538 patients in eight atezolizumab-treated cancer clinical trials across three cancer types (non-small-cell lung cancer, bladder transitional cell carcinoma, and renal cell carcinoma) were included. The whole cohort was randomly split into development and validation cohorts in a 7:3 ratio. Machine-learning algorithms (extreme gradient boosting, random forest, logistic regression with lasso regularization, support vector machine, and K-nearest neighbor) were applied to develop prediction models. Model performance was mainly assessed by area under the receiver operating characteristic curve (AUC) value, calibration plot, and decision curve analysis. The probability of death risk was then stratified. RESULTS: One thousand and three hundred and seventy-nine (54.33%) patients died. The random forest (RF) model was overall the best in terms of predictive performance, with the AUC of 0.844 (95% confidence interval [CI]: 0.826-0.862) in the development cohort and 0.786 (95% CI: 0.754-0.818) in the validation cohort for predicting mortality. Twelve baseline variables contributing to mortality prediction in the RF model were C-reactive protein, PD-L1 level, cancer type, prior liver metastasis, derived neutrophil-to-lymphocyte ratio, alkaline phosphatase, albumin, hemoglobin, white blood cell count, number of metastatic sites, pulse rate, and Eastern Cooperative Oncology Group (ECOG) performance status. A total of 1782 (70.2%) patients were separated into the high-risk and 756 (29.8%) low-risk groups. Patients in the high-risk group were significantly more likely to die, experience disease progression, discontinue study, and discontinue treatment than patients in the low-risk group (all p values < 0.001). Risk groups were not associated with immune-related adverse events and grades 3-5 treatment-related adverse events (all p values > 0.05). CONCLUSION: RF model has good performance in mortality prediction and risk stratification for cancer patients receiving atezolizumab monotherapy.

Prostate Cancer Risk and Prognostic Influence Among Users of 5-Alpha-Reductase Inhibitors and Alpha-Blockers: A Systematic Review and Meta-Analysis.

We systematically assessed the effect of 5-alpha-reductase inhibitors (5-ARIs) and/or alpha-blockers use on prostate cancer (CaP) incidence and outcomes, including CaP pathologic progression, CaP-specific mortality, and all-cause mortality. 5-ARIs but not alpha-blockers decreased risk of overall CaP, low grade CaP (Gleason < 7), and delayed CaP pathologic progression. Both 5-ARIs and alpha-blockers had no significant impact on risk of high grade CaP (Gleason ≥ 7), CaP-specific mortality, or all-cause mortality. Our result suggested that finasteride should be given for at least 4 years if used for preventing CaP.

A nomogram for predicting survival and retroperitoneal lymph node dissection treatment in patients with resected testicular germ cell tumors.

BACKGROUND AND OBJECTIVES: To build nomogram incorporating potential prognostic factors for predicting survival outcomes of testicular germ cell tumors (TGCT) patients after resection of the primary tumor. METHODS: Data of TGCT patients from the Surveillance, Epidemiology, and End Results database (2010-2016) who underwent resection of the primary tumor were collected. Overall survival (OS) and cancer-specific survival (CSS) were analyzed by using Cox regression models, nomogram, Kaplan-Meier method, and log-rank test. RESULTS: We identified 7272 TGCT patients. Age at diagnosis, histology, tumor size, American Joint Committee on Cancer (AJCC) staging system, and number of metastases sites were independent prognostic factors and were integrated into nomograms. The nomograms had higher C-indexes for both OS and CSS compared with the AJCC 7th staging system (0.881 vs 0.831 and 0.895 vs 0.856, respectively). Moreover, the new stratification of risk groups based on the nomograms showed a more significant distinction between Kaplan-Meier curves for survival outcomes than the AJCC staging system. Retroperitoneal lymph node dissection was associated with statistically improved survival probability in the nomogram middle-risk group in resected TGCT patients. CONCLUSION: The novel nomogram-based staging system could provide satisfactory risk stratification and survival prediction ability beyond traditional AJCC staging systems.

Effect of phosphodiesterase type 5 inhibitors on prostate cancer risk and biochemical recurrence after prostate cancer treatment: A systematic review and meta-analysis.

Recent studies have examined the impact of phosphodiesterase type 5 inhibitors (PDE5-Is) use on the risk of prostate cancer, and biochemical recurrence (BCR) in prostate cancer patients, but the results were inconsistent. A meta-analysis was conducted to assess the associations with all published studies. Databases (PubMed, Web of Science and MEDLINE) were retrieved to identify relevant studies which explored the impact of PDE5-Is use on the risk of prostate cancer, and BCR in prostate cancer patients. The summary results along with 95% confidence intervals (CIs) were calculated. Nine articles were eligible for the inclusion criteria. The pooled analysis showed that PDE5-Is use was not related to the increased risk of prostate cancer (odds ratio (OR), 0.71; 95% CI, 0.40-1.29). Moreover, PDE5-Is use was not linked to BCR risk in prostate cancer patients with erectile dysfunction (ED) following radical prostatectomy or radiation therapy (relative risk (RR), 1.09; 95% CI, 0.89-1.34). The heterogeneity test suggested moderate heterogeneity across studies. PDE5-Is use does not influence the risk of prostate cancer, and BCR in prostate cancer patients. More well-designed studies are warranted to confirm the findings of our analyses.

Safety and efficacy of Ofatumumab in chronic lymphocytic leukemia: a systematic review and meta-analysis.

OBJECTIVES: Increasing numbers of clinical studies have been carried out to investigate the therapeutic effect of Ofatumumab for patients with chronic lymphocytic leukemia (CLL) but no studies have yet reported a pooled estimate of the treatment effect. We performed a meta-analysis of evidence from 13 clinical trials to assess effectiveness and safety of Ofatumumab-based therapy in patients with CLL. METHODS: Relevant publications from PubMed, Web of Science, Embase, and ClinicalTrials.gov were searched. The primary efficacy outcomes were progression-free survival (PFS) and overall survival (OS). The second endpoint was the adverse events. RESULTS: The pooled efficacy analysis showed that there were no significant difference in PFS [hazard ratios (HR) = 0.88, 95% confidence interval (CI) = 0.47-1.63, p = 0.677, I2 = 94.9%] and OS (HR = 0.97, 95% CI = 0.70-1.36, p = 0.878, I2 = 58.7%) between Ofatumumab-based therapy and non-Ofatumumab therapy. The pooled toxicity analysis showed that Ofatumumab-based therapy was associated with an increased risk of infusion-related reaction but decreased risk of thrombocytopenia and anemia compared with non-Ofatumumab-based therapy. Moreover, infections, and infusion-related reaction occurred more frequently in participants with single Ofatumumab studies. DISCUSSION: Our analysis showed PFS was statistically significantly improved with Ofatumumab-based treatments (including Ofatumumab alone, Ofatumumab plus chemotherapy) for CLL compared with observation or chemotherapy-based regimen groups. Ofatumumab had no statistically significant improvement on the OS of patients with CLL. The Ofatumumab-based therapy could generally decrease the risk of adverse effects except infusion-related reaction and infections.

Chinese medicine as complementary therapy for female infertility.

Chinese medicine (CM) has been used in clinical treatment for thousands of years in China, Japan, Korea, and other countries. CM is at present attracting many attentions around the world for reproductive health care and disease prevention, including treatment of female infertility. This review focuses on the CM treatment for female infertility patients, and supplies a summary on the efficacy, safety, and mechanism of some Chinese herbal medicines, herbal medicine-derived active compounds, and acupuncture. A large number of researches have reported that CM could alleviate or even cure female infertility by regulating hormone, improving reproductive outcome of in vivo fertilization, affecting embryonic implantation, curing polycystic ovarian syndrome, endometriosis, pelvic inflammatory disease, relieving mental stress, and regulating immune system. Meanwhile, a few studies claimed that there was little adverse reaction of CM in randomized controlled trials. However, up to present there is a lack of adequate evidences with molecular mechanistic researches and randomized controlled trials to prove the CM as an effective and safe treatment for infertility. Thus, utility of CM as a complementary medicine will be a feasible method to improve the outcome of female infertility treatment.

Controversies regarding and perspectives on clinical utility of biomarkers in hepatocellular carcinoma.

The prevalence of hepatocellular carcinoma (HCC) worldwide parallels that of persistent infection with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV). According to recommendations by the World Health Organization guidelines for HBV/HCV, alpha-fetoprotein (AFP) testing and abdominal ultrasound should be performed in routine surveillance of HCC every 6 mo for high-risk patients. These examinations have also been recommended worldwide by many other HCC guidelines over the past few decades. In recent years, however, the role of AFP in HCC surveillance and diagnosis has diminished due to advances in imaging modalities. AFP was excluded from the surveillance and/or diagnostic criteria in the HCC guidelines published by the American Association for the Study of Liver Diseases in 2010, the European Association for the Study of the Liver in 2012, and the National Comprehensive Cancer Network in 2014. Other biomarkers, including the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-γ-carboxyprothrombin, Dickkopf-1, midkine, and microRNA, are being studied in this regard. Furthermore, increasing attention has focused on the clinical utility of biomarkers as pre-treatment predictors for tumor recurrence and as post-treatment monitors. Serum and tissue-based biomarkers and genomics may aid in the diagnosis of HCC, determination of patient prognosis, and selection of appropriate treatment. However, further studies are needed to better characterize the accuracy and potential role of these approaches in clinical practice.

Sorafenib-based combined molecule targeting in treatment of hepatocellular carcinoma.

Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase III studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/mTOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations.

Downregulation of p38 MAPK involved in inhibition of LDL-induced proliferation of mesangial cells and matrix by curcumin.

Curcumin, as a main pharmacological component in the traditional Chinese medicine-turmeric, has shown anti-inflammatory, anti-oxidation, anti-tumor and anti-fibrotic effects. This study aimed to investigate the possible underlying signaling pathway which was involved in the inhibition of LDL-induced proliferation of mesangial cells and matrix by curcumin. Rat mesangial cells in vitro were incubated with low-density lipoprotein (LDL) and different concentrations of curcumin (0, 6.25, 12.5, 25.0 µmol/L) or p38 MAPK inhibitor, SB203580 (10 µmol/L). Under LDL incubation, mesangial cells proliferated, the expression of MMP-2 mRNA and protein was decreased, the expression of COX-2 mRNA and protein was increased, reactive oxygen species (ROS) generation was increased and p38 MAPK was activated significantly (P<0.05). When LDL-induced cells were treated with curcumin in the concentration of 12.5 or 25.0 µmol/L, LDL-induced proliferation of mesangial cells was suppressed, the expression of MMP-2 mRNA and protein increased, the expression of COX-2 mRNA and protein downregulated, the production of ROS inhibited and p38 MAPK inactivated (P<0.05). In conclusion, curcumin can inhibit the LDL-induced proliferation of mesangial cells and up-regulate the expression of MMP-2, which may be related with the inhibitory effect of curcumin on COX-2 expression, ROS production and p38 MAPK.

Epidemic characteristics of hand, foot, and mouth disease in Shanghai from 2009 to 2010: Enterovirus 71 subgenotype C4 as the primary causative agent and a high incidence of mixed infections with coxsackievirus A16.

BACKGROUND: Enterovirus 71 (EV71) has been the main causative agent of hand, foot, and mouth disease (HFMD) outbreaks in recent years. A significant increase in the number of HFMD cases in China over the last 3 y has made the public prevention and therapy of this disease a critical issue. METHODS: A total of 3208 HFMD patients in Shanghai during the period 2009 to 2010 were analyzed; 437 clinical specimens were collected for the determination of causative pathogens. Eight of the isolated EV71 strains were sequenced and phylogenetically analyzed. RESULTS: The widespread outbreak of HFMD in Shanghai was caused predominantly by EV71 (86.5%), and in part by coxsackievirus A16 (CA16) (6.9%). The high incidence of mixed infections with EV71 and CA16 (17.6% of the total CA16-infected cases) has never before been observed in China. Most HFMD patients (76.9%) were aged 1-4 y. Boys showed a higher HFMD prevalence rate (65.3%) than girls (34.7%). Phylogenetic analysis on the basis of the VP1 gene and the complete genome sequences revealed that the EV71 strains that circulated in Shanghai belonged to the C4 subgenotype. CONCLUSIONS: EV71 subgenotype C4 was the major causative agent of the HFMD outbreak in Shanghai. A high incidence of mixed infections with EV71 and CA16 was also observed.

Simple and rapid detection of human enterovirus 71 by reverse-transcription and loop-mediated isothermal amplification: cryopreservation affected the detection ability.

Human enterovirus 71 (EV71) is the primary pathogen of hand, foot, and mouth disease (HFMD). EV71 infection may lead to neurologic damage, with higher incidence of fatality compared with other HFMD pathogens. An effective drug or vaccine against EV71 infection is currently unavailable. It is desirable to determine the pathogen of HFMD accurately and quickly for early treatment. In the current study, reverse-transcription and loop-mediated isothermal amplification (RT-LAMP) technology were developed to detect EV71. The efficacy of detecting EV71 was compared with regular nested reverse-transcription polymerase chain reaction (RT-PCR). After detecting 108 clinical specimens, results showed that RT-LAMP can specifically detect EV71, but not Coxsackie virus A16, and exhibited a specificity of 100% and a sensitivity of 97.1%, which was higher than regular RT-PCR. The findings indicate that RT-LAMP is a practical method for EV71 diagnostic applications, particularly in small county institutes of medical service. The detection ability of RT-LAMP was significantly affected by cryopreservation as the clinical specimens were repeatedly subject to freezing and thawing treatments.

Ketamine and lornoxicam for preventing a fentanyl-induced increase in postoperative morphine requirement.

BACKGROUND: N-methyl-D-aspartate receptor antagonists and nonsteroidal anti-inflammatory drugs are believed to prevent opioid-induced hyperalgesia and/or acute opioid tolerance, which could cause an increase in postoperative opioid requirement. In this randomized, double-blind, placebo-controlled study, we investigated whether co-administration of ketamine or lornoxicam and fentanyl could prevent the increase of postoperative morphine requirement induced by fentanyl alone. METHODS: Ninety females undergoing total abdominal hysterectomy with spinal anesthesia were randomly assigned to six groups consisting of placebo (normal saline, C), fentanyl (three bolus of 1 microg x kg(-1), F), ketamine (infusion of 15 microg x kg(-1) x min(-1), K), ketamine and fentanyl (infusion of 15 microg x kg(-1) x min(-1) ketamine plus three bolus of 1 microg x kg(-1) fentanyl, FK), lornoxicam (one bolus of 8 mg, L), and lornoxicam and fentanyl (one bolus of 8 mg lornoxicam plus three bolus of 1 microg x kg(-1) fentanyl, FL). Cumulative morphine consumption, pain score, and adverse effects were recorded at 1, 3, 6, 12, 24, and 48 h postoperatively. RESULTS: Cumulative morphine consumption in Group F was significantly more than that in Group C at 3, 6, and 12 h postoperatively (P < 0.05). Postoperative cumulative morphine consumption was similar in Groups C, K, FK, L, and FL. No differences in postoperative pain scores were observed among groups. More patients in Groups K and FK had hallucinations during and/or after surgery than those in Group C (P < 0.05). CONCLUSIONS: Our data suggest that the increase of postoperative morphine requirements induced by intraoperative administration of fentanyl could be prevented by ketamine or lornoxicam.